DK172397B1 - 5-Amino-8-phenyl-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one compounds, pharmaceutical preparation and use of the derivatives for the preparation of pharmaceutical preparation - Google Patents

Description

DK 172397 B1

The present invention relates to novel organic compounds and more particularly to novel 5- (substituted amino) -8- (phenyl or substituted phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one derivatives, 5 which are useful as agents for the treatment of cognitive and related neural behavioral disorders in mammals.

The novel compounds of the present invention have the following structural formula

10 o --- N

K 3 -1 R 4 1 R 5 15 Ab R 2 R 20 wherein R 1 and R 2 are each selected from hydrogen, ((C 1-4) alkyl, benzoyl, mono- or disubstituted benzoyl, wherein the substituents are (C -C 8) -alkyl, (C 1 -C 6) -alkoxy, (C 2 -C 7) -acyloxy, halogen, nitro or trifluoromethyl, and groups of the formula

II II II H

-C-CF3, -C-CHg-Cl, -C-O-CH2CH3, -C-OCHgCC13,

or - <CH2> „-R

Wherein n is an integer of 1-3 and R is hydroxy, 4-morpholinyl, 1H-imidazol-1-yl, -CH- [(C] -C3) alkoxy] 2 > ar-hydroxybenzyl, phenyl or mono- or disubstituted phenyl wherein the substituents are halogen or (O 2 -C 5) alkyl, R 1 9 R 5 together with the nitrogen to which they are attached are 4-morpholinyl or a group having the formula -N (CH 2) m wherein m is an integer of 2-6, R 3 is hydrogen or (C 1 -C 6) alkyl, R 4 is hydrogen, halogen, (C 1 -C 3) alkyl, (C 2 -C 3) ) -alkoxy or trifluoro-methyl, and R 5 is hydrogen or (C 1 -C 6) -alkyl. As far as the present invention is concerned, halogen may be fluorine, chlorine, bromine or iodine.

The present invention also relates to novel compositions containing an effective amount of the above-defined, novel 5- (substituted amino) -8- (phenyl or substituted phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaph thylen-3-one compounds useful as agents for the treatment of cognitive and related neural behavior disorders in mammals, and the use of the compounds of formula I for the preparation of pharmaceutical compositions for the treatment of cognitive and related neural behavior disorders.

The novel compounds of the present invention can be obtained as white to brown crystalline materials with characteristic melting points and absorption spectra. They are generally soluble in organic solvents such as trifluoroacetic acid or dimethylsulfoxide and the like, and are heavily soluble in solvents such as N, N-dimethylformamide or chloroform and the like, but are generally insoluble in water.

The novel 5- (substituted amino) -8- (phenyl or substituted phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one compounds of the present invention can be readily prepared as described. in the following reaction schemes.

35 3 DK 172397 B1

Scheme 1 «4 — k J] R4 ~ f {l]

R R * | N * 8H3CN

r5 —Hg-S-4> · <^> s'N ^ 'NC ^ pR3 is acetic acid. ^ - cn s ^. - —- L conh2 acid N (8> N <7> 10 / v.

β <· 0 "= fi V * 3 ^ -τ — l CONHg 15 R <6>

R4 N ------ p- Rj H

\ / iT I Γ N = v II / = M NaH / THF

Rg-Vs ^ Nv ^^ 1 ”| ^ \ -C- N ^ J -78eC

S ¢ 5) <4> - 20

H

/ 1 + R, -N-R2 (2)

v IN NaOH / OOF

\ X30X H202 «4 N -__ ^ | -R3- * 4 y ^ ULj" R3 sch3 Rj-N-R2 <3> 7Qoq *., - 2-¾ A <!> (2) m 4 DK 172397 B1 wherein R 1, R 2, R 3, R 4 and R 5 have the above meaning.

In accordance with the reaction scheme (Scheme 1) above, a suitable 7-substituted pyrazolo [1,5-a] pyrimidine-3-carbonitrile (8), prepared as described in the present specification and in U.S. Pat.

No. 4,236,005 to the corresponding 7-substituted pyrazolo [1,5-a] pyrimidine-3-carboxamide (7) by reaction with a strong mineral acid such as sulfuric acid, followed by reaction with water, whereupon all excess acid was neutralized. The 3-carbox-10-amide compound (7) is then reacted with sodium cyanoborohydride by stirring in glacial acetic acid under nitrogen in an ice bath for approx. 1 hour and then at room temperature for 1-12 hours. The resulting precipitate is collected, washed with water, dissolved in an inert solvent such as dichloromethane or acetonitrile and the like, and washed with a saturated solution of sodium bicarbonate. Separation and evaporation of the organic phase gives 4,5-dihydro-7-substituted pyrazolo [1,5-a] pyriraidin-3-carboxamide intermediate compound (6), which is recrystallized from solvents such as isopropyl alcohol or acetonitrile and the like, or from a mixture of solvents such as ether-hexane, chloroform-methanol or Ν, Ν-dimethylformamide-acetonitrile and the like.

The reduced 7-substituted pyrazolo [1,5-a] pyrimidine-3-carboxamide (6) in an inert solvent such as dry tetrahydrofuran or p-dioxane and the like is stirred with a strong base such as sodium hydride, lithium diisopropyl amide or potassium amide, under nitrogen or argon at a temperature of approx. -78 ° C bath) for 20 minutes to 3 hours, then add 1,1'-thiocarbonyldiimidazole (5) or thiophosgene 30, and the reaction mixture is stirred in the cold for 1-3 hours and then allowed to warm to room temperature with stirring for 24 hours. -48 hours. The reaction is quenched with water and the reaction mixture neutralized to a pH of 7.0 with 5% aqueous hydrochloric acid. The 4,5-dihydro-5-thioxo-8- (substituted) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one compound (4) is recovered by precipitation or by extraction with a B1 solvent such as chloroform or ether and the like, after which the solvent is evaporated. To a solution of the 5-thioxo compound (4) in a solvent such as N, N-dimethylformamide and the like is added 1 equivalent of 1N sodium 5 hydroxide, the reaction mixture is cooled to 0 ° C in an ice bath and 3 equivalents are added dropwise 30% hydrogen peroxide. The reaction mixture is stirred at 0 ° C for approx. 30 minutes, after which a suitable primary aliphatic amine selected from e.g. ethanolamine, methylamine, ethylamine, isopropylamine, 10 n-butylamine, isobutylamine, aminoacetaldehyde dimethylacetal, isopropylamine, 2-methylbenzylamine, 4-chlorobenzylamine, benzylamine, sec-butylamine, 2-amino-1-phenyl-ethanol, N- (2- amino-ethyl) -morpholine, 1-imidazolylpropylamine and the like, or a cyclic secondary amine such as pyrrolidine or piperidine and the like are added in one portion, and the stirred reaction mixture is allowed to warm to room temperature for several hours and then filtered for collecting the precipitated 5 - [(substituted) amino] -8-phenyl or [(substituted) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one-product (1), which is washed with water and then with ether.

Alternatively, the 5-thioxo compound (4) is dissolved in a solvent such as dry tetrahydrofuran and the like, whereupon the solution is stirred with sodium hydride at 0 ° C for approx.

15 minutes and this mixture is treated with an excess of 25 methyl iodide and allowed to warm to room temperature with stirring for 3 hours. The reaction is then quenched with water and the mixture is extracted in a solvent such as chloroform and the like. Evaporation of the solvent gives the 5-methylthio-8 (substituted) -3H, 6H-1,4,5a, 8a-tetraazaacet-naphthylene-3-one compound (3). The 5-methylthio compound (3) is suspended in a primary aliphatic amine such as benzylamine or 4-chlorobenzylamine and the like, and the mixture is heated at 70 ° C for 12-48 hours. The reaction mixture is cooled and then filtered to collect the solid which is washed with ether to give 5 - [(substituted) amino] -8-phenyl- or [(substituted) phenyl] -3H, 6H-1.4, The 5a, 8a-tetra-azaacenaphthylen-3-one product (1).

5 Scheme 2 R, _0

10 * VW

I) -1- COHHg N <6)

H \ NiH / THF

cnb / V7000 d N. R4 H. i— R · »15 ^ / τΗ \ (i)

RgC 1 / Δi / Dry THF (Β2) 2ο 20 / Base X Δ R4 Μ Γ ~ Κ '> N ^ N "-rR3 25 5 1 ^

H-N-Rg \ / I I

Wrs ^ In h \ tori R2 is -c-och2-cci3 h-n-R2

ISLAND

II 0

τη OR -C-CHg-Cl II

In which R 2 is -C-CF 3 (1a) (1b) In accordance with Scheme 2, wherein R 3, R 4 and R 5 have the above meaning, the reduced 7-substituted pyrazolo [1, 5] is dissolved. a] pyrimidine-3-carboxamide (6), prepared as described in Scheme 1, in dry tetrahydrofuran and cooled to -78 ° C. The mixture is then treated with sodium hydride for approx. 30 minutes, after which cyanogen bromide is added and reacted at -78 ° C for approx. 4 hours and then at room temperature for 16 hours. The reaction mixture is diluted with water and the product (1) wherein R 1 and R 2 are both hydrogen are collected by filtration and then washed with water and ether.

When a suspension of the product (1) in dry tetrahydrofuran is heated at reflux for 16 hours in the presence of [1,8-bis (dimethylamino) naphthalene, Ν, Ν, Ν ', Ν'-tetramethyl-1,8-naphthalenediamine] and an acid chloride such as 2,2,2-trichloroethyl chloroformate or chloroacetyl chloride and the reaction quenched with water yields the products (1a).

When the above product (1) is suspended in an acid anhydride such as trifluoroacetic anhydride and heated at reflux for approx. 24 hours, then the reaction mixture is filtered and the precipitate is washed with ether and chloroform and the organic solution is separated, washed with saturated sodium bicarbonate, dried and concentrated to give the product 1b.

25 30 35 8 DK 172397 B1

Scheme 3 5

r <O.

j + r2n = c = s r3 -r3 10 I J-L Γ.-NH »/ (11) II / H <6> /

'. "ISLAND

15

L N

r5 -r3 I I-Lr-NH.

II

in 0 c = s

20 nh \ n »0H

Re CH 2 (<10)

r <-O

- R = -m!

Va 8l ”/ c-sch3

s II

R * Μ ~ Γ ~ 83 ^ / -K !, i> 0 R C9> 30 ('' Vlf TY ** wr5-jl ^ Y "hn-r2 (1) 35 9 DK 172397 B1 In accordance with Scheme 3, wherein 1 * 3, R 4 and R 5 are as defined above, a suitably substituted reduced 7-substituted pyrazolo [1,5-a] pyrimidine-3-carboxamide (6) prepared as described in Scheme 1 is reacted with an excess of a suitable R 2 isothiocyanate (11) such as benzoyl isothiocyanate in dry acetone under nitrogen The mixture is heated at reflux for about 20 hours, cooled and filtered to give 4 - [(benzoylamino) thioxo-methyl] -pyrazolo [ The 1,5-a] pyrimidinecarboxamide (10) The compound (10) in Ν, Ν-dimethylformamide is combined with 1N sodium hydroxide and then treated with methyl iodide to give the corresponding -4 (5H) -carboimidothioic acid methyl ester (9) from the aqueous mixture The methyl ester (9) in p-dioxane in the presence of 7N sodium hydroxide is refluxed for several hours and then neutralized with 6N hydrochloric acid to precipitate the desired [3-oxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] benzamide product (1).

Alternatively, a suitable carboxamide (6) in dry tetrahydrofuran is cooled to -78 ° C and stirred with sodium hydride 20 for approx. Then add an appropriate isothiocyanate (11), such as ethoxycarbonyl isothiocyanate, and stir the reaction mixture at -78 ° C for several hours. Stirring is then continued at room temperature for 48 hours. The reaction is quenched with water, the mixture is extracted with ether and the aqueous layer is neutralized with 5% hydrochloric acid and extracted with a solvent such as chloroform to give the desired product (1).

The novel compounds of the present invention are capable of enhancing neural function in warm-blooded animals suffering from behavioral neurological problems, including the cognitive impairment associated with diminished neural function associated with cerebral insufficiency, aging. , dementia and similar conditions.

A useful in vivo trial that measures how effective drugs acting on the central nervous system enhance survival in a hypoxic environment, presumably by improving the energy-to-demand ratio, is known as "The Hypoxic Survival test ". This experiment demonstrates the activity of the test compound relative to a known reference compound such as physostigmine. This trial demonstrates the increased survival of 5 test animals in a hypoxic environment after treatment, a drug compared to control animals treated with saline-free drug. Extensive experiments have shown that under conditions of 10% oxygen, only 5-20% of control mice (treated with saline) survive 10 after 5 minutes, whereas 60-80% of mice treated with the reference compound survive. Drugs are tested by intraperitoneally injecting groups of mice 30 minutes before placing them in a hypoxic mixture and survival is measured. The logical rationale for this trial is that drugs that enhance survival under hypoxic conditions without concomitant depression or sedative side effects may do so by promoting energy metabolism or by maintaining normal brain function under conditions of reduced energy metabolism. Due to the brain's dependence on a constant supply of energy, drugs having this property can have many far-reaching therapeutic indications, including post-stroke recovery and internal head injury, as well as diminishing the damaging effects of the aging central nervous system. Eg. It is known that energy metabolism in aged 25 and senile dementia patients is deficient and is thought to contribute significantly to the neurochemical and neurophysiological dysfunctions of aging.

Groups of 20 Royal Hart mice (6-8 weeks old) are given test compound intraperitoneal injections, usually 30 at 10 and 100 mg / kg 30 minutes before being placed in a hypoxic mixture (10% oxygen, 90% carbon dioxide), and after 5 minutes, survival is measured. At times, further testing may require doses ranging from 1-200 mg / kg.

A separate group of 20 mice is given intraperitoneally 35 saline injections (0.01 cm 3 / g body weight) and treated as described above.

11 DK 172397 B1

Another group of 20 mice is given intraperitoneal injections with a known active dose of the reference compound, e.g. 0.125 mg / kg physostigmine and treated as described above.

The results of this test for representative of compounds of the present invention are given in Table I.

Table I

10 Hepoxic Survival Trial

Dose% Over-

Compound mg / kg of [3-Oxo-8- [3- (trifluoromethyl) phenyl] - 100 40 3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] carbamic acid ethyl ester 5- ( 2-Methylpropyl) -8- [3- (trifluoro-methyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 5-Amino-8- [3- (trifluoromethyl) ) -phenyl] - 50 60 3H, 6H-1, 4,5a, 8a-tetraazaacenaphthylene-100 67.5 3-one 200 60 25 N- [3-Oxo-8- [3- (trifluoromethyl) phenyl] - 45 3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-100 70 5-yl] -3- (trifluoromethyl) benzamide 3-Nitro-N- [3-oxo-8- [3- (trifluoromethyl) benzamide 100 70-thyl) -phenyl] -3H, 6H-1,4,5a, 8a-tetra-azaacenaphthylen-5-yl] -benzamide 3,4-Dichloro-N- [3-oxo-8- [3- (trifluoro (100 60 [5 (methyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazacenaphthylen-5-yl] benzamide

Table I (continued)

Hvpoxislc survival trial

Dose% Over-

Compound mg / kg of living 5 --- 5-Ethylamino-8- [3- (trifluoromethyl) -phenylphenyl] -3H, 6H-1,4,5a, 8a-tetraazaacanaphthylen-3-one 2.2 , 2-Trifluoro-N- [3-OXO-8- [3- (tri-42.5 fluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] -acetamide [3-Oxo-8- [3- (trifluoromethyl) phenyl] -1 H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] -2,2,2-trichloroethyl ester carbamic acid 5- [(2,2-Dimethoxyethyl) amino] -8- [3- 100 60 (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 5 - [[2- (4-Morpholinyl) -ethyl] -amino] -8-100 [3- (trifluoromethyl) -phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 5 - [(2- Hydroxy-2-phenylethyl) amino] -8-42,5 [3- (trifluoromethyl) phenyl] -3H, 6H-100 70 1,4,5a, 8a-tetraazaacenaphthylen-3-one 5 - [( 2,2-Dimethoxyethyl) -amino] -8-55-phenyl-3H, 6H-1,4,5a, 8a-tetraaza-50-acenaphthylen-3-one 100-5 (butylamino) -8-phenyl 3H, 6H- 50 40 l, 4,5a, 8a-tetraazaacenaphthylen-3-one 100 70 200 60 13 DK 172397 B1

Table I (continued)

Hvooxian survival trial

Dose% Over-

Compound mg / kg of living 5 - 5- (Ethylamino) -8-phenyl-3H, 6H-100 72.5 l, 4.5a, 8a-tetraazaacenaphthylen-3-one 200 65 5 - [[(4-Chlorophenyl ) -Methyl] -amino] - 100 55 10 8- [3- (Trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 5 - [(2-Hydroxyethyl) -amino ] -8-phenyl-100 60 3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 5- (methylamino) -8-phenyl-3H, 6H-100 95 1,4,5a, 8a tetraazaacenaphthylen-3-one 5- (Butylamino) -8- [3- (trifluoromethyl) - 100 57,5 phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacene-naphthylen-3-one 5- [ [(2-Hydroxyethyl) amino] -8- [3- 100 80 (trifluoromethyl) phenyl] -3H, 6H- 1,4,5a, 8a-tetraazaacenaphthylen-3-one 5 "Ct (2-Methylphenyl) -methyl] -amino] - 47.5 30 8- [3- (trifluoromethyl) -phenyl] -3H, 6H-52.5 l, 4.5a, 8a-tetraazaacenaphthylen-3-one 100 70 5- ( Ethylamino) -8- (3-fluorophenyl) - 10 55 3H, 6H-1,4,5a, 8a-tetraazaacenaphthyl-100 55 35 en-3-one 14 DK 172397 B1

Another in vivo trial associated with diminished neural function in mammals is "The Passive-Avoidance Anoxic-Induced-Amnesia Test". This experiment is used to determine the attenuation of anoxia-induced memory loss in drug-treated mice compared to control animals treated with drug-free saline.

A shock-motivated single-test-see-passive-avoidance procedure is used. Groups of 25 middle-aged (9-month-old) mice ("Royal Hart" and "Taconic Farms"), 10 are placed individually in the front room of a 2-room box and are allowed to enter the back room by themselves. As soon as the mouse enters the back compartment, a door automatically closes the animal inside, causing a mild electric shock (0.4 mA for 4 seconds) in the feet. Following this shock, the mouse is placed to begin with in an anoxic environment (0% oxygen) for 12 seconds, which quickly induces unconsciousness. The animals are then placed in a hypoxic environment (15% oxygen) for 4 minutes, causing the mice to regain slowly. All testing is performed 24 hours later and in all cases 20 the mice appear to have recovered completely from the previous anoxic / hypoxic treatment. All test compounds are administered intraperitoneally at doses of 10-200 mg / kg (depending on active doses in previous trials) 30 minutes prior to training and testing. Control animals are injected intraperitoneally with only 25 saline in an amount of 0.01 cm 3 / g body weight.

The propensity to enter the back room is recorded for both learning and testing. The more the animal remembers the shock, the more it will probably avoid going into the back compartment and the longer it will last before it enters again.

30 A 30% improvement over saline control values is considered active. The result of this test for representative compounds of the present invention is shown in Table II.

35 15 DK 172397 B1

Table II

Passive avoidance test for anoxia-induced memory loss

Dose% For-

Compound mg / kg improvement 5 - 5- (2-Methylpropyl) -8- [3- (trifluoro-43.5 methyl) phenyl] -3H, 6H-1, 4.5a, 8-100 158, 0 tetraazaacenaphthylen-3-one 5-Amino-8- [3- (trifluoromethyl) -5,8,8 phenyl] -3H, 6H-1,4,5a, 8a-tetra-51.8 azaacenaphthylen-3-one 100 53.5 5- (Butylamino) -8-phenyl-3H, 6H-15, 4,5a, 8a-tetraazaacenaphthylene-64.3 3-one

The compounds of the present invention have been found to be useful as agents for treating cognitive and related neural behavioral problems in mammals when administered in amounts ranging from ca. 5 mg to approx. 200 mg / kg body weight per day. day. A preferred dose range for optimum results is from ca. 10 mg to approx. 50 mg / kg body weight per day. per day, and such dosage units are used that a total amount of about 700 mg to approx. 3.5 g of active compound to an individual with a body weight of approx. 70 kg in a 24 hour period.

The dose range described above for the treatment of neural behavioral problems in mammals can be regulated to provide the optimal therapeutic response. Eg. multiple doses may be administered daily, or the dose may be proportionally reduced as indicated by the requirements of the therapeutic situation. It is a definite practical advantage that these active compounds can be administered in any convenient manner, e.g. orally, intravenously, intramuscularly or subcutaneously.

The active compounds can be administered orally, e.g.

16 DK 172397 B1 with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules or compressed into tablets or they may be incorporated directly with the diet.

For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, lozenges, lozenges, capsules, elixirs, suspensions, syrups, waffles and the like. Such materials and compositions should contain at least 0.1% active compound. The percentage of the materials and compositions can, of course, be varied, and may conveniently be from about 10%. 2 to approx. 60% by weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dose is obtained. Preferred materials or compositions of the present invention are prepared such that an oral dosage unit form contains between 5 and 200 mg of active compound.

Tablets, lozenges, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, a disintegrant such as corn starch, potato starch, alginic acid and the like, a lubricant such as magnesium stearate, and a sweetener such as sucrose, lactose or saccharin, or a flavoring agent such as peppermint, winter vegetable oil or cherry flavoring. When the dosage unit form is a capsule, it may, in addition to materials of the above type, contain a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit 30. Eg. tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methyl and propyl parabens as preservatives, a colorant and flavoring such as cherry and orange flavoring. Of course, any material used in the preparation of each dosage unit form 17 should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained release preparations.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in 10 glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under general storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection applications include sterile aqueous solutions or dispersions and sterile powder for on-site preparation of sterile injectable solutions or dispersions. In all cases, the mold must be sterile and must be liquid to such an extent that it is easy to use in syringe. It must be stable under the conditions of manufacture and storage and must be protected against the pollutant effect of microorganisms, e.g. bacteria and fungi. The carrier material may be a solvent or dispersion medium, e.g. water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The invention will be described in more detail in the following specific examples.

Example 1 7- [3- (Trifluoromethyl-phenyl-pyrazolone-5-pyrimidine-3-carboxamide)

A mixture of 3.0 g of 7- (a, a, a-trifluoro-m-tolyl) -pyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in U.S. Patent No. 4,236. 005) and 150 ml of concentrated sulfuric acid are stirred at room temperature for 4 hours. The solution 18 GB 172397 B1 is then gently poured into ice water with stirring. The white precipitate formed is collected, washed with water and then with saturated sodium bicarbonate until neutral. The solid is heated with 1 liter of isopropyl alcohol and filtered.

The white solid is dried in vacuo to give the desired product as a colorless solid, m.p. 256-258 "C.

Example 2 7-Phenylpyrazolo [1,5-a] pyrimidine-3-carboxamide

A mixture of 4.0 g of 7-phenylpyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 7 of U.S. Patent No. 4,236,005) and 40 ml of concentrated sulfuric acid is stirred at room temperature for 16 hours. The solution is then poured into ice with stirring, and the mixture is carefully made just basic with concentrated ammonium hydroxide. The solid is collected by filtration and recrystallized from dichloromethane to give pale yellow needles, m.p. 236-238,5eC.

20

Example 3 4,5-Dihydro-7-phenylpyrazolori-5-alpyrimidine-3-carboxamide 6.0 g of 7-phenylpyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 2) are stirred under nitrogen. as a suspension in 120 ml of glacial acetic acid (cooled in an ice bath), then 3.5 g of sodium cyanoborohydride is added portionwise to the reaction mixture. After stirring for 1 hour in the ice bath, the mixture is stirred at room temperature for 3.5 hours, at which time the original solid dissolves. Stirring is continued for 1 hour, then the solution is concentrated in vacuo. Water is added to the residue and a precipitate is formed. The precipitate is collected by filtration and then dissolved in dichloromethane. The organic solution is washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated in vacuo to give a solid. The solid is recrystallized from isopropyl alcohol to give 5.0 g of the desired product as a white solid, m.p. 149-152 ° C.

Example 4 4.5 4,5-Dihydro-7-β- (trifluoromethyl-phenyl-pyrazolori-5-alpha-pyrimidine-3-carboxamide 10.0 g of 7- [3- (trifluoromethyl) -phenyl] -pyrazolo [1,5-a ] pyrimidine-3-carboxamide (prepared as described in Example 1) is stirred under nitrogen as a suspension in 120 ml of glacial acetic acid (cooled in an ice bath), then 5.5 g of sodium cyanoborohydride is added to the reaction mixture in portions with an additional 80 ml of glacial acetic acid. After stirring for 1 hour in the ice bath, the mixture is stirred at room temperature for 19 hours, the solution is evaporated to dryness, then water is added and the white precipitate formed is collected by filtration and washed with an aqueous saturated solution of sodium bicarbonate and then with water. Substance is treated with 100 ml of acetonitrile and collected by filtration and dried to give 5.25 g of the desired product which is recrystallized from acetonitrile, mp 157-160 ° C.

Example 5 7- (3-Fluorophenyl) pyrazolone-5-pyrimidine-3-carboxamide 131.5 g of 7- (m-fluorophenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. Patent No. 4,236,005) is dissolved in 500 ml of concentrated sulfuric acid by stirring at room temperature for 18 hours. The solution is then carefully poured into ice water. The precipitate which is formed is collected by filtration and then washed with 1N sodium hydroxide until a pH of 7 is reached, then washed with water to remove the excess base. The crystalline material is dried in vacuo to give 136.3 g of the desired product as yellow crystals, m.p. 247-249 * 0th

35 20 DK 172397 B1

Example 6 7- (3-Fluorophenyl) -4,5-dihydropyrazolori-5-alpyrimidine-3-carboxamide 136.3 g of 7- (3-fluorophenyl) -pyrazolo [1,5-a] pyrimidine-5-3-carboxamide (prepared as described in Example 5) in 1 liter of glacial acetic acid is stirred at room temperature, then 83.6 g of sodium cyanoborohydride are added portionwise under nitrogen. The mixture is stirred for 16 hours, after which the precipitated crystals are collected by filtration and triturated with saturated sodium bicarbonate until a pH of 7-8 is reached. The crystals are washed with water and dried in vacuo to give 63.0 g of the product as cream colored crystals with m.p. 122-125'C.

Example 7 4,5-Dihydro-8-phenyl-5-thioxo-3H.6H-1.4.5a.8a-tetraazaacet-naphthylene-3-one

A mixture of 7.6 g of 4,5-dihydro-7-phenyl-pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 3) in 304 ml of dry tetrahydrofuran is stirred and cooled by stirring. -78 ° C (dry ice, acetone) under nitrogen and 2.17 g of sodium hydride (60% s dispersion in mineral oil) is added. The mixture is stirred at -78 ° C for 30 minutes, then 4.84 g of 1,1'-thiocarbonyldiimidazole is added in one portion. The temperature is maintained at -78 ° C for 2 hours, then allowed to slowly warm to room temperature. while stirring is continued for 48 hours, quench the reaction with 500 ml of water and neutralize to a pH of 6-7 with 5% aqueous hydrochloric acid, forming a crystalline solid which is collected by filtration, triturated with ether, filtered and dried to give 3.2 g of the desired product as white crystals, mp 289-291 ° C.

35 21 DK 172397 B1

Example 8 4,5-Dihydro-5-thioxo-8- [3- (trifluoromethyl) -phenyl-3H.6H-1.4.5a.8a-tetraazaacenaphthylene-3-one

To a stirred solution of 1.00 g of 4,5-dihydro-7- [3-5 (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 4 ) in 30 ml of dry tetrahydrofuran cooled to -78 ° C (dry ice-acetone) is added 286 mg of 60% sodium hydride (dispersion in mineral oil). The reaction mixture is stirred at -78 ° C for 30 minutes, then 637 mg of 1,1'-thiocarbonyldiimidazole are added. The mixture is allowed to warm slowly to room temperature and stirred for 36 hours. The reaction is quenched with water, the mixture is neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gives 934 mg of the desired product as a yellow solid, m.p. 251-258 * c (decomposition).

Example 9 5- [Methylthiol-8- [3- (trifluoromethyl-phenyl-3H, 6H-1.4.5a, 8a-20-tetraazaacenaphthylene-3-one

To a solution of 100 mg of 4,5-dihydro-5-thioxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacet-naphthylen-3-one (Example 8 ) in 10 ml of dry tetrahydrofuran cooled at 0 ° C is added 13 mg of sodium hydride (60% dispersion 25 in mineral oil). The reaction mixture is stirred at 0 ° C for 15 minutes, then an excess of methyl iodide is added. The mixture is allowed to warm to room temperature and then stirred for 3 hours. The reaction is quenched with water and the mixture is extracted with chloroform. Evaporation of the extract in vacuo gives 47 mg of the desired product as a yellow solid, m.p. 234-237 ° C (decomposition).

35 22 DK 172397 B1

Example 10 8- (3-Fluorophenyl-4,5-dihydro-5-thioxo-3H, 6H-1,4,5a, 8a-tetra-azaacenaphthylene-3-one

A mixture of 63.0 g of 7- (3-fluorophenyl) -4,5-dihydro-5-pyrazolo [1,5-a] pyrimidine-3-carboxamide (Example 6) and 2.5 liters of dry tetrahydrofuran is stirred and cooled to -78 ° C in a dry ice-acetone bath to which 18.0 g of sodium hydride (60% dispersion in mineral oil) is added in one portion. This mixture is stirred at -78 ° C for 1 1/2 hours, then 40.0 g of 1,1'-thiocarbonyldiimidazole is added and stirring is continued at -78 ° C for 2 hours. The mixture is allowed to warm to room temperature and stirred for 48 hours, then quench the reaction with 2.5 liters of water and neutralize with 5% aqueous hydrochloric acid. The crystalline solid which is formed is collected, washed with ether and dried to give 54.6 g of the desired product as cream colored crystals with syrup. 298-300eC.

Example 11 N- [3-Oxo-8- [3- (trifluoromethyl] -phenyl-3H, 6H-1,4.5a, 8a-tetraaza-acenaphthylene-5-yl-benzamide

To a stirred solution of 3,08 g of 4,5-dihydro-7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide (Example 4) in 30 ml dry acetone under nitrogen 25 add 1.5 ml of benzoyl isothiocyanate to 5 ml of dry acetone. The mixture is heated at reflux for 3 hours, then an additional 4.5 ml of benzoyl isothiocyanate is added and the mixture is heated at reflux for 16 hours. The mixture is cooled to room temperature and the solid precipitate formed is collected by filtration and washed with ether to give 600 mg of 4 - [(benzoylamino) thioxomethyl] -4,5-dihydro-7- [3- (trifluoromethyl) ) -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide, m.p. 210-212 "C. To a stirred mixture of 1.5 g of the above product (prepared as described above), 30 ml of Ν, Ν-dimethylformamide and 2.0 ml of 1N sodium hydroxide are added 4.0 ml of methyl iodide. This mixture is stirred at room temperature for 3 hours, then an additional 1.0 ml of 1 N sodium hydroxide and 2.0 ml of methyl iodide are added and stirring is continued. After 1 hour, the addition of 1.0 ml of sodium hydroxide and 2.0 ml of methyl iodide is repeated and stirring is completed within 1 hour of this addition. The mixture is mixed with water and the solid precipitate is collected by filtration, washed with water and dried in vacuo to give 1.4 g of 3- (aminocarbonyl) -N-benzoyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-4 (5H) -carboximidothioic acid methyl ester with m.p. 172-175eC.

To a stirred mixture of 1.66 g of the above compound (prepared in the manner described above) in 30 ml of p-dioxane is added 30 ml of 7N sodium hydroxide. This mixture is heated at reflux for 2 hours. The two-layer mixture 15 is cooled and then neutralized to a pH of 7.0 with 6N hydrochloric acid. The solid formed is collected by filtration, washed with water and dried. Recrystallization from acetonitrile gives 510 mg of N- [3-oxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] benzamide as a white solid fabric with m.p. 235-239eC.

Example 12 [3- (Aminocarbonyl) -7- [3- (trifluoromethyl-H-phenyl-pyrazolo-1,1,5-a] pyrimidin-4 (5H) -vi-1-thioxomethyl-1-carbamic acid ethyl-ester

To a stirred solution of 3,0 g of 4,5-dihydro-7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 4 ) In 90 ml of dry tetrahydrofuran cooled to -78 ° C, 584 mg of sodium hydride (60% dispersion in mineral oil) is added in one portion. The reaction mixture is stirred at -78 ° C for 1 hour, then 2.55 g of ethoxycarbonyl isothiocyanate is added. The mixture is stirred at -78 ° C for 2 hours, then allowed to slowly warm to room temperature. The reaction mixture is stirred at room temperature for 48 hours, then quenched with water and extracted with ether. The aqueous layer is separated, neutralized with 5% hydrochloric acid and extracted with chloroform. The chloroform extracts are evaporated in vacuo to give the desired product as a yellow solid.

Example 13 Γ 3-Oxo-8-Γ 3- (Trifluoromethyl) -phenyl) -3H.6H-1,4,5a,8a-tetra-azaacenaphthylene-5-yl-carbamic acid ethyl ester

To a stirred solution of 300 mg of [[3- (aminocarbonyl) - 7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidin-4 (5H) -10 yl] -thioxomethyl] -carbamic acid Ethyl ester (Example 12) in 15.0 ml of dry tetrahydrofuran cooled in an ice bath at 0 ° C is added 30 mg of sodium hydride (60% dispersion in mineral oil) in one portion. After gas evolution has ceased, the mixture is stirred for an additional 30 minutes at 0 ° C, then 15 ml of methyl iodide is added and the reaction mixture is allowed to warm to room temperature with stirring for 2 hours. The reaction is quenched with water and diluted in water. The aqueous solution is extracted with chloroform. The chloroform extracts are combined and evaporated in vacuo and the residue is triturated with ether. The solid is collected by filtration to give the desired product as a white solid, m.p. 219-220eC.

Example 14 5- (2-Methylpropylΐ-8-β-trifluoromethyl) -phenyl-3H, 6H, 1,4,5a, 8a-tetraazaacenaphthylene-3-one

To a solution of 500 mg of 4,5-dihydro-5-thioxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacet-naphthylen-3-one (prepared as described in Example 8) Into 10.0 ml of Ν, Ν-dimethylformamide is added 1.5 ml of 1 N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath, then 0.5 ml of 30% hydrogen peroxide is added dropwise to the mixture. The reaction mixture is stirred at 0 ° C for 30 minutes, then 1.0 ml of isobutylamine is added in one portion and the mixture is allowed to warm to room temperature, then stirred for 2 hours. The solid is collected by filtration and washed with water and then ether to give 223 mg of the desired product as a white solid, m.p. 266-268 ° C. Following the procedure of Example 14 and reacting 4,5-dihydro-5-thioxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-5, 4,5a, 8a-tetraazaacenaphthylen-3-one with an appropriate primary aliphatic amine or cyclic secondary amine are obtained from the products of Examples 15-27 as set forth in Table III.

Table III

10 Ex. Amine Product Syrup, ° C

Pyrrolidin 5- (1-Pyrrolidinyl) -8- [3- 255-256 (trifluoromethyl) -phenyl] - (decomp.) 3H, 6H-1,4,5a, 8a-tetraaza-acenaphthylen-3-one 16 Isopropylamine 5- [(1-Methylethyl) amino] - 257-260 8- [3- (Trifluoromethyl) - (decomposition) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 17 Aminoacetal-5 - [(2,2-Dimethoxyethyl) - 220-221 dehyde dimino] -8- [3- (trifluoro (decomp.) Thylacetal methyl) -phenyl] -3H, 6H-1.4, 5α, 8α-Tetraazaacetaphnylethylene-3-one 18 Sec.butyl 5- [(1-Methylpropyl) amino] - 245-247.5 Amine 8- [3- (Trifluoromethyl) - (decomp.) Pherryl] -3H, 6H-1, 4,5a, 8a-tetraazaacenaphthylen-3-one 19 Piperidine 5- (1-Piperidinyl) -8- [3- 259-261 (trifluoromethyl) phenyl] - (decomp.) 3H , 6H-1, 4,5a, 8a-tetraaza-acenaphthylen-3-one DK 172397 B1 26

Table III (continued)

Ex. Amine Product Mp., "C

N- (2-Amino-5- [[2- (4-methylbrolinyl) -241-143-ethyl) -methyl-ethyl] -amino] -8- [3- (tri- (decomp.) Pholine fluoromethyl) -phenyl] - 3H, 6H-1,4,5a, 8a-tetra-azaacenaphthylen-3-one 21 2-Amino-1- 5- [(2-Hydroxy-2-phenyl-266-267 phenylethanol ethyl) - amino] -8- [3- (tri- (decomp.) fluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetra-azaacenaphthylen-3-one 22 n-Butylamine 5- (Butylamino) -8- [3- (tri-257-259 fluoromethyl) -phenyl] -3H, 6H- (dec.) 1,4,5a, 8a-tetraazaacene naphthylen-3-one 23 Ethanolamine 5 - [((2 -Hydroxyethylamino] - 247.5-249 8- [3- (Trifluoromethyl) - (dec.) Phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 24 Methylamine 5- ( Methylamino) -8- (3- (tri-288-290 fluoromethyl) -phenyl] -3H, 6H- (dec.) 1,4,5a, 8a-tetraazaacet-naphthylen-3-one 2-Methylbenzene - [[(2-Methylphenyl) - 277-280 zylamine methyl] amino] -8- [3- (decomp.) (Trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraaza Acenaphthylen-3-one

Table III (continued)

Ex. Amine Product mp, ° C

Moxpholine 5- (4-Morpholinyl) -8- [3- 240-243 5 (trifluoromethyl) phenyl] - (dec.) 3H, 6H-1,4,5a, 8a-tetraaza- acenaphthylen-3-one 27 Diethylamine 5-Ethylamino-8- [3- (trifluoromethyl) phenyl] - (decomp.) 3H, 6H-1,4,5a, 8a-tetra-azaacenaphthylene-3 -one

Example 28 5- [(Phenylmethyl) -amino] -8- [3-] trifluoromethyl-phenyl] -3H. 6H-1,4,5a, 8a-tetraazaacenaphthylene-3-one 200 mg of 5- (methylthio) -8- [3-trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3- one (prepared as described in Example 9) is suspended in 10.0 ml of benzylamine.

The reaction mixture is cooled to room temperature and filtered.

The solid on the filter is washed with ether and air dried to give 189 mg of the desired product as a white solid, m.p. 220-224 ° C.

Example 29 5-Amino-8- [3- (trifluoromethyl) -phenyl] 1-3H. 6H-1.4.5a. 8a-tetra- azaacenaphthvlen-3-one

To a stirred solution of 556 mg of 4,5-dihydro-7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 4) in 25 ml of dry tetrahydrofuran under nitrogen cooled to -78 ° C (dry ice, acetone) is added 159 mg sodium hydride (60% dispersion in mineral oil) in one portion. After stirring the mixture at -78 ° C for 30 minutes, 191 mg of cyanogen bromide is added in one portion. The temperature of the reaction mixture is kept at -78 ° C for 4 hours, after which the mixture is allowed to warm to room temperature for 16 hours. The mixture is diluted with water and the solid which is separated is collected and washed with water and ether to give the product as a brown solid, m.p. 287-289 ° C (decomposition).

Example 30 2.2.2-Trifluoro-N-β-oxo-8-β- (trifluoromethyl) phenyl1-3H.6H-1,4.5a.8a-tetraazaacenaphthylene-5-yl-acetamide 750 mg 5-amino-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) is suspended in 20.0 ml of trifluoroacetic anhydride and this mixture is heated at reflux for 24 hours. The reaction mixture is filtered and the removed precipitate is washed with ether and chloroform. The filtrate is extracted with ether and chloroform, and the combined organic solution is washed with saturated sodium hydrogen carbonate, dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give 627 mg of the desired product as a white solid, m.p. 184-185'C.

Example 31 2-Chloro-N- [3-oxo-8- [3- (trifluoromethyl-phenyl-3H, 6H-1.4.5a, 8a-tetraazaacenaphthylene-5-yl) -acetamide 500 mg 5-amino-8 - [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) is suspended and stirred in 30 ml of dry tetrahydrofuran, whereupon 1 equivalent (0.322 g) of [1,8-bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine] ("Proton Sponge") is added followed by 1, 1 equivalents (0.187 g) of chloroacetyl chloride. The reaction mixture is heated at reflux for 16 hours and then allowed to cool to room temperature. The mixture is poured into 200 ml of water and the resulting precipitate is collected by filtration to give 423 mg of the desired product as a brown solid, m.p. 189-192 ° C (dec.).

35 DK 172397 B1 29

Example 32: 3-OXO-8-[3- (trifluoromethyl-phenyl] -3H, 6H-1,4, 5a, 8-tetra-azaacenaphthylene-5-yl-carbamic acid-2,2,2-trichloroethyl ester 500 mg 5-amino-8- [3- (Trifluoromethyl) phenyl] -3H, 6H-5, 4,5a, 8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) is suspended and stirred in 25.0 ml of dry tetrahydrofuran and then added. 320 mg of [1,8-bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine] ("Proton Sponge") followed by 0.207 ml of 2.2.2 This mixture is heated at reflux for 16 hours, quenched by pouring into 200 ml of water and the precipitate formed is collected by filtration to give 419 mg of the desired product as a white solid, mp 225-226 * c.

15

Example 33 4-Methoxy-N-β-3- (8- (3-trifluoromethyl) -phenyl-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-5-yl) -benzamide 200 mg 5-amino-8- [3 - (Trifluoromethyl) phenyl] -3H, 6H-20 l, 4,5a, 8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) is suspended in 3 ml of pyridine, to which 0.2 ml of p-methoxybenzoyl chloride is added. in one portion and the reaction mixture is stirred at room temperature for 16 hours. The reaction is quenched in 100 ml of water and the solid formed 25 is collected by filtration and washed with ether to give 164 mg of the desired product as a white solid, m.p. 271-273 ° C.

Using the procedure of Example 33 and reacting 5-amino-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one with an appropriate acid chloride the products of Examples 34-42 are obtained as given in Table IV.

35

Table IV

Ex. Acid chloride Product Snp., ° C

3-Trifluoro-N- [3-chloro-8- [3- (trifluoro-methylbenzoylmethyl) -phenyl] -3H, 6H-chloride 1,4,5a, 8a-tetraazaace - naphthylen-5-yl] -3- (trifluoromethyl) benzamide p-Toluoyl-4-methyl-N- [3-oxo-8- [3- 278-280 chloride (trifluoromethyl) phenyl] - 3H, 6H-1,5, 8a-tetraaza-acenaphthylen-5-yl] -benzamide 36 2-Acetoxy-2- (Acetyloxy) -N- [3-OXO-8- 232-236 benzoyl- [3 - (trifluoromethyl) -phloro-nyl] -3H, 6H-1, 4,5a, 8a-tetraazaacenaphthylen-5-yl] -benzamide 37 Ehenoxyacene-N- [3-oxo-8- [3- (trifluoro) 180-182 (methyl chloride (methyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacetanaphthylen-5-yl] -2-phenoxyacetamide 38 3,5-Dime-3,5-methoxy-N - [3-oxo-8- 270-272 thoxybenzoyl- [3- (trifluoromethyl) chloride phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] -benzamide 35

Table IV (continued)

Ex. Acid Chloride Product Srtp., 'C

31 Nitroben-3-Nitro-N- [3-oxo-8- [3- 235-239 5-acyl chloride (trifluoromethyl) phenyl] - 3H, 6H-1,4,5a, 8a tetraaza-acenaphthylen-5-yl] -benzamide 4-Bromo-4-brcin-N - [3-OXO-8 - [3- 269-274 benzoyl- (trifluoromethyl) -phenyl] - (decomp.) chloride 3H, 6H-1,4,5a, 8a-tetraazacenaphthylen-5-yl] -benzamide 41 3,4-Dichloro-3,4-Dichloro-1- [3-σχο-8- 256-260 benzoyl - [3- (trifluoromethyl) chloride phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-20 y] 1-benzamide 42 4-Fluoro-4-Fluoro-N- [3-OXO -8- [3- 267-269 phenylbenz (trifluoromethyl) phenyl] zylchloride 3H, 6H-1,4,5a, 8a-tetraaza-aoenaphthylen-5-yl] -benzamide

Example 43 5 - [((4-Chlorophenyl) -methyl] amino] -8- [3-trifluoromethyl) -phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3-one 400 mg 5- (methylthio) - 8- [3- (Trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (prepared as described in Example 9) in 25.0 ml of 4-chlorobenzylamine is heated at 70 ° C for 36 hours. The precipitate formed is collected by filtration to give the desired product as a white solid, m.p. 281-282eC.

32 DK 172397 B1

Example 44 5- [(2-Methylpropyl) -amino 1-8-phenyl-3H. 6H-1,4,5a, 8a-tetra-azaacenaphthylene-3-one

To a solution of 500 mg of 4,5-dihydro-8-phenyl-5-5 thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (readily prepared as described in Example 7) for 10, 0 ml of Ν, Ν-dimethylformamide is added 1.8 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath, and 0.6 ml of 30% hydrogen peroxide is added dropwise to the mixture. The reaction mixture is stirred at 0 ° C for approx. For 30 minutes, then 1.0 ml of isobutylamine is added in one portion and the mixture is allowed to warm to room temperature, then stirred for 2 hours.

The solid is collected and washed with water and then ether to give 253 mg of the desired product as a white solid, m.p. 265-268 * 0 (decomposition).

Using the procedure of Example 44 and reacting 4,5-dihydro-8-phenyl-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one with a suitable primary aliphatic amine or cyclic secondary amine, the products of Examples 45-51 are obtained as set forth in Table V.

Table V

Ex. Amine Product Mp., "C

45 Aminoacetal-5- [(2,2-Diethethoxyethyl) - 223 dehyde-dimino] -8-phenyl-3H, 6H-thylaoetal 1,4,5a, 8a-tetraazaacet-naphthylen-3-one 46 n -Butylamine 5- (Butylamino) -8-phenyl-268-271 3H, 6H-1,4,5a, 8a-tetraaza (dec.) Aoenaphthylen-3-one 47 ammonia / 5-Amino-8-phenyl 3H, 6H-291-294 methanol 1,4,5a, 8a-tetraazaacet (decomp.) Naphthylen-3-one

Table V (continued)

Ex. Amine Product Sirp., 'C

33 DK 172397 B1 48 70% ethyl 5- (Ethylamino) -8-phenyl-290-291 5 amine / water 3H, 6H-1,4,5a, 8a-tetra- (dec.) Azaacenaphthylene-3-an 49 Isopropylamine 5- [(Methylethyl) amino] - 278-279.5 8-Phenyl-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3-one Ethanolamine 5- [(2-Hydroxyethyl) - 177 -178 amino] -8-phenyl-3H, 6H- (dec.) 1,4,5a, 8a-tetraazaacanaphthylen-3-one 51 40% methyl-5- (methylamino) -8-phenyl-265- 268 amine / water 3H, 6H-1,4,5a, 8a-tetra- (dec.) 20 azaanaphthylene-3-one

Example 52 8- (3-Fluorophenyl) -5-Γ (2-methylpropyl) amino 1-3H, 6H-1.4.5a, 8a-tetraazaacenaphthylene-3-one To a solution of 3.00 g of 8- (3- fluorophenyl) -4,5-dihydro-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (Example 10) in 60.0 ml of Ν, Ν-dimethylformamide is added 10 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath, then dropwise 3.40 ml of 30% hydrogen peroxide is added to the mixture, the reaction mixture is stirred at 0 ° C for 30 minutes, then 6.0 ml of isobutylamine is added in one portion and the mixture is allowed to warm to room temperature, then stirred for 2 hours. The solid is collected by filtration, washed with water and then ether to give 1.24 g of the desired product as a white solid, mp 256 -259 * C.

Using the procedure of Example 52 and substituting 8- (3-fluorophenyl) -4,5-dihydro-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3 on with a suitable primary aliphatic amine or cyclic secondary amine, the products of Examples 53-57 are obtained as set forth in Table VI.

5

Table V

Ex. Amine Product mp, ° C

53 n-Butylamine 5- (Butylamino) -8- (3- 255-257 fluorophenyl) -3H, 6H- 1,4,5a, 8a-tetraazaaoe naphthylen-3-one 54 Sec. butyl 8- (3-Fluorophenyl) -5 - [(1- 260-263 amine-methylpropyl) amino] -3H, 6H-1,4,5a, 8a-tetraaza-acenaphthylen-3-one 55 70% aqueous 5- (Ethylamino) -8- (3-fluoro-285-287 ethylamine phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one 56 Aminoacetal-5- [(2,2-Dimethoxyethyl) ) - 204-208 dehydro-dimino] -8- (3-fluorophenyl) -thylacetal 3H, 6H-1,4,5a, 8a-tetraaza-acsenaphthylen-3-one ) -5- [(1- 262-264 amine methylethyl) amino] -3H, 6H- 1,4,5a, 8a-tetraazaacenaphthylen-3-one 35 172397 B1

Example 58 8- [3-Fluorophenyl] -5-[(3- (1H-imidazol-1-yl) -propyl] amino] -3H6H-1.4.5a.8a-tetraazaacenaphthylen-3-one

To a stirred solution of 10.0 g of 8- (3-fluorophenyl) -5 4,5-dihydro-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one in 300 ml Ν, Ν-Dimethylformamide is added 18.75 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath for 30 minutes, then 6.25 ml of 30% hydrogen peroxide is added dropwise to the mixture. The mixture is stirred at 0 ° C for 1 hour and 30 minutes, then 12.5 ml of N- (3-aminopropyl) imidazole is added in one portion. The mixture is allowed to warm to room temperature for 32 hours. The mixture is filtered to remove the solid which is washed with water. The filtrate and washing liquid are evaporated in vacuo to give a yellow solid. The solid is dissolved in 250 ml of chloroform, to which 100 ml of water is added to form a precipitate. The layers are separated and the precipitate is collected by filtration to form a white solid. The solid is recrystallized from dimethyl sulfoxide and dried in vacuo 20 at 60 ° C to give 1.1 g of the desired product as a white solid, m.p. 256-258 ° C.

Example 59 5-β 3- (1H-Imidazol-1-yl) -propyl-amino-1-8-phenyl-3H. 6H-25 1.4.5a.8a-tetraazaacenaphthylene-3-one

To a stirred solution of 5.0 g of 4,5-dihydro-8-phenyl-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one (Example 7) in 200 ml of Ν, Ν -dimethylformamide is added 9.37 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath for 30 minutes, then dropwise adding 3.125 ml of 30% hydrogen peroxide. After stirring the mixture at 0 ° C for an additional 30 minutes, 6.25 ml of N- (3-aminopropyl) imidazole is added in one portion. Then, the reaction mixture is allowed to warm to room temperature for 24 hours. The solvent is evaporated in vacuo and a yellow oil is obtained. The oil is mixed with 250 ml of chloroform and the mixture is transferred to a separatory funnel. The organic layer is separated, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated in vacuo and a yellow oil is obtained. This oil is triturated with ether to precipitate a white solid. The solid 5 is collected by filtration, recrystallized from dimethyl sulfoxide and ether (2: 1) and dried in vacuo at 70 ° C to give 500 mg of the desired product as a white solid, m.p. 238-240 ° C.

Example 60 5-Amino-8- (13-fluorophenyl) -3H.6H-1.4.5a.8a-tetraazaacenaoh-thylene-3-one

To a stirred suspension of 5.0 g of 7- (3-fluorophenyl) 4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carboxamide (Example 15 6) in 250 ml of dry tetrahydrofuran cooled to -78 ° C (dry ice, acetone) is added 1.70 g of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture is stirred at -78 ° C for 30 minutes, then 2.05 g of cyanogen bromide is added, and the mixture is stirred for an additional 2 hours at -78 ° C and then allowed to warm slowly to room temperature for 16 hours. with water and the solid is collected by filtration, washed with water and then ether to give 376 mg of the desired product as a white solid.

25

Example 61 N- [3-Oxo-8- (3- (trifluoromethyl 1) -phenyl] -3H, 6H-1.4.5a, 8a-tetra-azaacenaphthylene-5-yl-4-phenylmethyl) -1-piperazine acetamide 1,000 g of 2-chloro-N- [3-oxo-8- [3- (trifluoromethyl) -phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] -acetamide (prepared as described in Example 31) is dissolved in 50 ml of dry tetrahydrofuran and then 430 mg of 1-benzyl-piperazine is added to the mixture in one portion. The reaction mixture is heated at reflux for 16 hours. The mixture is cooled, basified with 1N sodium hydroxide and extracted with chloroform. The solvent is evaporated and the solid is purified as usual to give 426 mg of the desired product as a brown solid.

Example 62 5-Methyl-5- [1- (1-methylethyl) -aminol-8-3- (trifluoromethyl) -phenyl] -3H.6H-1.4.5a.8a-tetraazaacenaphthylene-3-one

Using the procedure described in Example 2, 27.6 g of 6-methyl-7- (3- (trifluoromethyl) phenyl) -pyrazolo [1,5-a] pyrimidine-3-carbonitrile (described in U.S. Pat. 18.7 g of 6-methyl-7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxamide, m.p. 237-239 AD.

The above product (18.7 g) is dissolved in 200 ml of glacial acetic acid by stirring for 1 hour under nitrogen in an ice bath, then 3.67 g of sodium cyanoborohydride is added portionwise to the reaction mixture under nitrogen. The solution is stirred for 4 hours and 30 minutes at room temperature and then evaporated in vacuo to give an oil. The oil is triturated with saturated sodium bicarbonate solution to a pH of 7.0.

The precipitate formed is collected by filtration, washed with water and dried. The solid is dissolved in 200 ml of ethyl acetate by heating on a steam bath, then hexane is added until crystals are formed. After cooling, the crystals are collected by filtration to give 22.0 g of 4,5-dihydro-6-25-methyl-7- [3- (trifluoromethyl) phenyl] -pyrazolo [1,5-a] pyrimidine-3 -carboxamide as white crystals with m.p. 200-202 ° C.

To a stirred suspension of 5.0 g of the above dihydro compound in 200 ml of dry tetrahydrofuran cooled to -78 ° C (dry ice, acetone) is added 1.43 g of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture is stirred at -78 ° C for 30 minutes, then 3,185 g of 1,1'-thiocarbonyldiimidazole is added in one portion. The stirred solution is kept at -78 ° C for 2 hours, then the reaction mixture is allowed to warm slowly to room temperature for 24 hours. The reaction is quenched with 500 ml of water and neutralized with 5% aqueous hydrochloric acid. The crystals formed at 38 DEG are collected and washed with ether to give 4.0 g of 4,5-dihydro-7-methyl-5-thioxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1 , 4,5a, 8a-tetraazaacenaphthylene-3-one as white crystals, m.p. 269-271 ° C.

To a stirred solution of 2.5 g of the above product in 150 ml of Ν, Ν-dimethylformamide is added 7.5 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath for 30 minutes, then 2.5 ml of 30% hydrogen peroxide is added dropwise and the mixture is stirred at 0 ° C for 1 hour.

10 ml of isopropylamine is added in one portion and the mixture is allowed to warm to room temperature for 72 hours.

The precipitate formed is collected by filtration, washed with water and then ether and dried to give 600 mg of the desired product as white crystals, m.p. 284-286eC.

15

Example 63 8- (4-Chlorophenyl-7-methyl-5- [2- (2-methylpropyl) -aminol-3H, 6H, 1,4,5a, 8a-tetraazaacenaphthylene-3-one

A mixture of 50.0 g of p-chloropropiophenone and 200 ml of 20 Ν, Ν-dimethylformamide-dimethyl acetal is stirred and heated at reflux for 28 hours. The reaction mixture is evaporated in vacuo to give a yellow oil. The oil is subjected to "Kugel-rohr" distillation. The residual oil from the distillation is collected and triturated with hexane to form 25 crystals. The solid is collected by filtration to give 21.5 g of 4'-chloro-3-dimethylamino-2-methyl-acrylophenone as yellow crystals, m.p. 45-47 * C.

A mixture of 21.5 g of the above compound, 10.368 g of 3-aminopyrazole-4-carbonitrile and 250 ml of glacial acetic acid is stirred and heated at reflux for 24 hours. The mixture is evaporated to dryness in vacuo to give brown crystals. The solid is triturated with saturated sodium hydrogen carbonate solution to give a pH of 7-8 and then filtered the mixture. The solid is washed with water and dried to give 25.2 g of 7- (4-chlorophenyl) -6-methyl-pyrazolo [1,5-a] pyrimidine-3-carbonitrile as light brown crystals 39 DK 172397 B1 with m.p. 154-157 ° C. A mixture of 18.8 g of the above compound and 100 ml of concentrated sulfuric acid is stirred at room temperature for 18 hours. The solution is then carefully poured into ice with stirring. The solid formed is collected by filtration and then neutralized with 1N sodium hydroxide, filtered and washed with water. The crystals are collected and dried to give 18.7 g of 7- (4-chlorophenyl) -6-methyl-pyrazolo [1,5-a] pyrimidine-3-carboxamide.

17.7 g of the foregoing product is dissolved in 200 ml of 10 acetic acid by stirring for 1 hour under nitrogen in an ice bath, then 3.8 g of sodium cyanoborohydride is added portionwise to the reaction mixture under nitrogen. The solution is stirred for 2 hours at room temperature and then evaporated in vacuo to give an oil. The oil is triturated with saturated sodium bicarbonate solution to a pH of 7.0. The precipitate formed is collected by filtration, washed with water and dried.

The solid is recrystallized from absolute ethanol to give 12.6 g of 7- (4-chlorophenyl) -4,5-dihydro-6-methyl-pyrazolo [1,5-a] pyrimidine-3-carboxamide as white crystals with 20 m.p. 210-2120C.

To a stirred suspension of 5.0 g of the above dihydro compound in 200 ml of dry tetrahydrofuran cooled to -78 ° C (dry ice, acetone) is added 1.43 g of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture is stirred at -78 ° C for 30 minutes, then 3,185 g of 1,1'-thiocarbonyldiimidazole is added in one portion. The stirred solution is kept at -78 ° C for 2 hours, then the reaction mixture is allowed to warm slowly to room temperature over 24 hours. The reaction is quenched with 500 ml of water and the mixture neutralized with 5% aqueous hydrochloric acid. The crystals which are formed upon standing are triturated with ether and filtered. The crystals are then added to a 1: 1 mixture of methanol and chloroform which is heated, cooled and filtered to give 4.2 g of 8- (4-chlorophenyl) -4,5-dihydro-7-methyl-5-35 thioxo -3H, 6H-1, 4.5a, 8a-tetraazaacenaphthylen-3-one as cream colored crystals, m.p. 283-285 ° C.

40 DK 172397 B1

To a stirred solution of 4.0 g of the above compound in 100 ml of Ν, Ν-dimethylformamide is added 7.5 ml of 1N sodium hydroxide. The reaction mixture is cooled to 0 ° C in an ice bath, then 2.5 ml of 30% hydrogen peroxide is added dropwise, and the mixture is stirred at 0 ° C for 1 hour. Then, 5 ml of isobutylamine is added in one portion and the reaction mixture is allowed to warm to room temperature for 48 hours. The solution is evaporated in vacuo to give a pale yellow solid. The solid is washed with water and then ether and dried to give 2.6 g of white solid. The solid is dissolved in 200 ml of isopropyl alcohol by heating, then cooled with scraping to precipitate the product. The product is collected by filtration to give 1.4 g of the desired product as a white solid, m.p. 283-285eC.

15

Example 64 5-(Butylamino) -2,7-dimethyl-8-phenyl-3H, 6H, 1,4,5a, 8a-tetra-azaacenaphthylene-3-one

A mixture of 57.0 g of propiophenone in 150 ml of N, N-dimethylformamide-dimethyl acetal is stirred and heated at reflux for 24 hours. Then, the solvent is removed in vacuo and a yellow oil is obtained. The oil is subjected to Kugelrohr® distillation to give 69.8 g of 3-dimethylamino-2-methylacrylo-phenone as a yellow oil, bp 100 ° C (0.050 mm Hg).

A mixture of 37.6 g of the above compound and 24.3 g of 5-amino-3-methyl-4-pyrazole-carbonitrile in 500 ml of glacial acetic acid is stirred and heated at reflux for 48 hours. The solution is evaporated in vacuo to give a brown solid. The solid is neutralized to a pH of 7.0 with saturated sodium bicarbonate solution, filtered, washed with water and dried. The solid is heated on a steam bath in 800 ml of absolute ethanol and filtered to give 11.2 g of 2,6-dimethyl-7-phenylpyrazolo [1,5-a] pyrimidine-3-carbonitrile as a white solid with mp. 208-210 * 0th

A mixture of 22.8 g of the above product (prepared in the manner described above) and 300 ml of concentrated sulfuric acid are stirred at room temperature for 24 hours. The solution is then carefully poured into ice to give a precipitate. The mixture is allowed to warm to room temperature and then filtered to give a yellowish solid.

The material is neutralized with 1 N sodium hydroxide to a pH of 7.0 and then washed with water and dried. The solid is heated in 900 ml of absolute ethanol and then filtered to collect 8.2 g of 2,6-dimethyl-7-phenylpyrazolo [1,5-a] pyrimidine-3-carboxamide as a white solid, m.p. 252-10 254 ° C. The filtrate is cooled and allowed to crystallize an additional 14.7 g of product, m.p. 252-254eC.

22.9 g of the above product are dissolved in 300 ml of glacial acetic acid with stirring under nitrogen in an ice bath, then 13.51 g of sodium cyanoborohydride are added portionwise to the reaction mixture. The reaction mixture is stirred at room temperature for 5 hours, then the solution is evaporated in vacuo to give an oil. The oil is neutralized with saturated sodium hydrogen carbonate solution to form a precipitate. The solid is collected by filtration, washed with plenty of water and dried. The solid is dissolved by heating in 6000 ml of absolute ethanol. The solution is filtered and the filtrate is cooled in an ice bath and scratched to precipitate a solid. The solid is collected by filtration and dried in vacuo to give 13.6 g of 4,5-dihydro-2,6-dimethyl-7-phenyl-pyrazolo [1,5-a] pyrimidine-3-carboxamide as white crystals with m.p. 208-210 ° C.

To a stirred suspension of 13.6 g of the foregoing dihydro compound in 600 ml of dry tetrahydrofuran cooled to -78 ° C (dry ice, acetone) is added 2.1 g of sodium hydride (60% 30 dispersion in mineral oil) in one portion. The reaction mixture is stirred at -78 ° C for 30 minutes, then 7.74 g of 1,1'-thiocarbonyldiimidazole are added in one portion. The stirred solution is kept at -78 ° C for 2 hours, then the reaction mixture is allowed to slowly warm to room temperature over 24 hours. The reaction is quenched with 500 ml of water and neutralized with 5% aqueous hydrochloric acid. Crystals are formed by stirring and they are collected by filtration. The solid is triturated with ether and then collected to give 9.7 g of 4,5-dihydro-2,7-dimethyl-8-phenyl-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene. 3-on as white crystals with m.p.

255-257 ° C.

To an unrefined solution of 4.5 g of the above

3-one compound in 200 ml of Ν, Ν-dimethylformamide is added 8.43 ml of 1N sodium hydroxide in one portion. The reaction mixture is cooled to 0 ° C in an ice bath, dropwise adding 2.8 ml of 30% hydrogen peroxide and the mixture is stirred at 0 ° C.

for 1 hour and 30 minutes. Then 5.62 ml of n-butylamine is added in one portion and the mixture is allowed to warm to room temperature over 48 hours. The solvent is evaporated in vacuo to give a white solid. The solid 15 is then subjected to flash chromatography on silica gel using 2% methanol / 98% chloroform as solvent system. The desired fraction is collected and evaporated in vacuo to give 400 mg of the desired product as a white solid, m.p. > 300 ° C.

20

Example 65 7-13-Methylphenyl-pyrazolo [1,5-alpyrimidine-3-carboxamide

A mixture of 7- (3-methylphenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 25 7 of U.S. Patent No. 4,236,005) and concentrated sulfuric acid is stirred at room temperature for 16 hours. hours. The solution is then carefully poured into ice with stirring and the mixture is carefully made just basic with concentrated ammonium hydroxide. The solid is collected by filtration to give 7- (3-methylphenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamide.

35 43 DK 172397 B1

Example 66 4.5- Dihydro-7- (3-methylphenyl) -pyrazoloT1. S-alpyrimidine-S-carboxamide 7- [3-methylphenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamine (prepared as described in Example 1) is stirred as a suspension in glacial acetic acid (cooled in an ice bath ) under nitrogen and then an excess of sodium cyanoborohydride is added portionwise to the reaction mixture. After stirring for 1 hour in the ice bath, the mixture is stirred at room temperature for 19 hours. The solution is evaporated to dryness, then water is added and the white precipitate formed is collected by filtration and washed with an aqueous saturated solution of sodium hydrogen carbonate and finally with water. The solid is collected by filtration and dried to give 4,5-dihydro-7- (3-methylphenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamide.

Example 67 4.5- Dihydro-5-thioxo-8- (3-methylphenyl) -3H.6H-1.4.5a.8a-tetraazaacenaphthylene-3-one To a stirred solution of 1.00 g of 4,5-dihydro-7 - (3-Methyl) -phenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 4) in dry tetrahydrofuran cooled to -78 ° C (dry ice-acetone) is added sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred at -78 ° C for 30 minutes, then 1,1'-thiocarbonyl-diimidazole is added. The mixture is allowed to warm slowly to room temperature and stirred for 36 hours. The reaction is quenched with water and neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gives 4,5-dihydro-5-thioxo-8- (3-methylphenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one.

35 44 DK 172397 B1

Example 68 8- (3-Methylphenyl-5 - [(2-methylpropyl) amino] -3H, 6H-1.4.5a, 8a-tetraazaacenaphthylene-3-one

To a solution of 8- (3-methylphenyl) -4,5-dihydro-5 5-thioxo-3H, 6H-1 to 4,5a, 8a-tetraazaacenaphthylen-3-one (Example 10) in Ν, Ν-dimethylformamide sodium hydroxide is added. The reaction mixture is cooled to 0 ° C in an ice bath and 30% hydrogen peroxide is added dropwise and the reaction mixture is stirred at 0 ° C for 30 minutes.

Isobutylamine is then added in one portion and the mixture is allowed to warm to room temperature and stirred for 2 hours. The solid product is collected by filtration, washed with water and water and then ether to give 8- (3-methyl-phenyl) -5- [(2-methylpropyl) amino] -3H, 6H-1,4,5a, 8a-tetraaza-15-acenaphthylen-3-one.

Example 69 7- (3-Methoxyphenyl) -Pyrazolori-5-pyrimidine-3-carboxamide

A mixture of 7- (3-methoxyphenyl) -pyrazolo [1,5-a] -20 pyrimidine-3-carbonitrile (prepared as described in U.S. Pat.

U.S. Patent No. 4,236,005) and concentrated sulfuric acid are stirred at room temperature for 4 hours, and the resulting solution is then poured into an ice-water mixture with stirring. The precipitate is collected and dried to give 7- (3-methoxyphenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamine.

Example 70 4,5-Dihydro-7- (3-methoxyphenyl) -pyrazolo [1,5-a] pyrimidine 7- (3-methoxyphenyl) -pyrazolo [5-a] pyrimidine-3-carboxamide (prepared as described in Example 2) Stir under nitrogen as a suspension in glacial acetic acid (cooled in an ice bath) and then an excess of sodium cyanoborohydride is added portionwise to the reaction mixture. After stirring for 1 hour in the ice bath, the mixture is stirred at room temperature for 3 hours and then the solution is concentrated in vacuo. Water is added to the residue and the precipitate formed is collected by filtration and then dissolved in dichloromethane. The organic solution is washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated in vacuo to give 4,5-dihydro-7- (3-5 methoxy-phenyl) -pyrazolo [1,5-a] pyrimidine as a solid.

Example 71 4.5-Dihydro-8- (3-methoxyphenyl) -5-thioxo-3H. 6H-1.4-5a. 8a-Tetraazaacenaphthylene-3-one A mixture of 4,5-dihydro-7- (3-methoxyphenyl) -pyrazolo [1,5-a] pyrimidine-3-carboxamide (prepared as described in Example 3) in Dry tetrahydrofuran is stirred and cooled at -78 ° C (dry ice, acetone) under nitrogen and two equivalents of sodium hydride (60% dispersion in mineral oil) are added.

The mixture is stirred at -78 ° C for 30 minutes, then 1,1'-thio-carbonyldiimidazole is added in one portion. The temperature is kept at -78 ° C for 2 hours, then the mixture is allowed to warm slowly to room temperature while stirring is continued for 48 hours. The reaction is quenched with water and the mixture is neutralized to a pH of 6-7 with 5% aqueous hydrochloric acid. A crystalline solid is formed which is collected by filtration, triturated with ether, filtered and dried to give 4,5-dihydro-8- (3-methoxyphenyl) -5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one.

25

Example 72 8- (3-Methoxyphenyl) -5- [2-methylpropyl) amino 1 -3H. 6 H-1.4.5a.8a tetraazaacenaphthvlen-3-one

By the method of Example 68, 8- (3-methoxyphenyl) -4,5-dihydro-5-thioxo-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one is reacted with isobutylamine to form of 8- (3-methoxyphenyl) -5- [(2-methylpropyl) amino] -3H, 6H-1,4,5a, 8a-tetraaza-acenaphthylene-3-one.

35

Claims (10)

46 5 17 -397 B1 1. 5-Amino-8-phenyl-3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one compounds, characterized in that they have the formula 5 R3-T = NN V'N'v _ ^ \ R4 i 10. R 5 N Ré 'Ri wherein and R 2 are each selected from hydrogen, (C 1 -C 4) -alkyl, benzoyl, mono- or disubstituted benzoyl, wherein the substituents are (C 1 -C 6) alkyl, (C - (C2-C7) -acyloxy, halogen, nitro or trifluoromethyl, and groups of the formula 000 and 20. II II II II -C-Cr3, -C-CHg-Cl, -CO-CHgCH2, Or where n is an integer of 1-3 and R is hydroxy, 4-morpholinyl, 1H-imidazol-1-yl, -CH [ (¢ 2 -O3) alkoxy] 2, α-hydroxybenzyl, phenyl or mono- or disubstituted phenyl, wherein the substituents are halogen or (C 1 -C 6) alkyl, R 2 and R 2 together with the nitrogen to which they are attached. is attached, is 4-morpholinyl or a group of the formula o. »wherein m is an integer of 2-6, R3 is hydrogen or (¢ 2 -C6) alkyl, R4 is hydrogen, halogen , ((C -033) alkoxy, (Οχ-C3) alkyl or trifluoromethyl, and R5 is hydrogen or (Οχ-Cg) alkyl. Compound according to claim 1, characterized in that it is 5- (2-methylpropyl) -8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one . Compound according to claim 1, characterized in that it is 5-amino-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one. Compound according to claim 1, characterized in that it is N- [3-oxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] -3- (trifluoromethyl) benzamide. A compound according to claim 1, characterized in that it is 3,4-dichloro-N- [3-oxo-8- [3-trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene 5-yl] -benzamide. Compound according to claim 1, characterized in that it is 5-ethylamino-8- [3- (trifluoromethyl) phenyl] - 3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one. Compound according to claim 1, characterized in that it is [3-oxo-8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-5-yl] carbamic acid -2.2-tri-chloroethyl. A compound according to claim 1, characterized in that it is 5- [2,2-dimethoxyethyl) amino] -8- [3- (trifluoromethyl) phenyl] -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylen-3-one. Pharmaceutical compositions, characterized in that they contain an effective amount of the compounds 30 according to claims 1-8. Use of the compounds of formula I according to claims 1-8 for the preparation of pharmaceutical compositions for the treatment of cognitive and related neural behaviors. 35